PT100641B - Process for the treatment with benzozepines, pharmaceutical compositions containing these benzozepines, benzozepine compounds and the process for their preparation - Google Patents

Abstract

The invention relates to a process for the treatment of neurological problems which comprises the administration to a mammal requiring such treatment of an effective quantity of compound of formula I or formula II <IMAGE> <IMAGE> in which R1, R2, R3 and R4 are independently selected from: hydrogen, (1-3C) perfluoroalkyl, halo, nitro and cyano, and R5 is a (1-5C) alkyl group or one of its pharmaceutically acceptable salts. The invention also relates to compounds and pharmaceutical compositions suitable for the treatment of neurological problems, and a process of preparation.

Description

DESCRIPTION í i · li · ·

Mastery of the Technique

The present invention relates to benz2 ”b_7azepine compounds useful for the treatment of neurological disorders generally in mammals such as man. More specifically, the compounds are useful for the treatment of attacks and / or other neurodegenerative disorders such as hypoglycemia, cerebral palsy, transient cerebral ischemic attack, perinatal asphyxia, epilepsy, psychosis, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease , Parkinson's disease, olivo-pontocerebellar atrophy, virus-induced neurodegeneration such as in ad- 1 -

chiridae and its associated dementias, anoxia such as drowning, trauma to the spinal cord, spine and brain, poisoning by endogenous neuro toxins, and chronic pain, for the prevention of drug and alcohol deficiency symptoms, and for inhibition of tolerance and dependence on opium painkillers. The present invention relates in particular to new benz / "b_7azepine compounds useful for the reduction of neurological degeneration such as that which can be induced by ata which is the irreparable functional damage that can result. Treatment using a compound of the present invention can be therapeutic, for example, by administering a compound following an ischemic event to mitigate the effects of that event. The treatment can also be prosthetic or prospective by administering a compound in anticipation of the occurrence of an ischemic event, for example in a patient liable to suffer an attack.

Background of the Invention

It is known that ischemic events can trigger a drastic increase in the extracellular concentrations of excitatory amino acids glutamate and aspartate which can, in turn, cause prolonged neuronic excitation leading to a massive influx of calcium from extracellular zones to intracellular zones in cells nerve cells in the brain. Therefore, a calcium overload can be created which leads to a cascade of events leading to the cell's catabolism and subsequently resulting in the cell's death. The K-methyl-D-aspartate receptor complex (1WDA) is believed to play a significant role in the cascade of events leading to cell necrosis following an ischemic event.

Approval of the Invention

The compounds provided by the present invention can be useful in a number of neurodegenerative disorders by

that act as excitatory amino acid antagonists. They can do this indirectly, by allosteric modulation of the glutamate binding site, specifically acting as strychnine-insensitive glycine receptor antagonists in the MM receptor complex. They can also do this directly by binding to the glutamate site itself in the NMDA receptor complex.

According to the present invention there is provided a method for the treatment of neurological disorders, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I or formula II (the formulas are presented, together with other formulas identified by roman numerals, on the pages that follow the examples), where r \ R ^, R ³ and R ^ are independently selected from: hydrogen, perfluoroalkyl- (1-3C), halo, nitro and cyan;

Pv is an alkyl- (1-50) group;

or a pharmaceutically acceptable salt thereof.

Thus, the present invention also provides a compound of formula I or formula II (as defined above), or a pharmaceutically acceptable salt thereof, for use in medicine; and in particular for use in the treatment of neurological disorders.

The present invention also provides for the use of a compound of formula I or II (as defined above), or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for the treatment of neurological disorders.

The present invention further provides

pharmaceutical compositions for the treatment of neurological conditions that contain a compound of formula I or formula II as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

Certain compounds of formula I are known from United Kingdom Patent Specification 1,340,334 and also from Birchall and Rees, Can. J. Chem., 52, 610 (1974). However, new compounds of the present invention include those of formula I and formula II in which R and R ⁷ are not (independently) selected from the group consisting of hydrogen and halogen in which R ¹ and R 4 are hydrogen.

If the theory is not to be limiting, it is believed that the compounds of the formula II can be converted into the 3-hydroxy derivatives in vivo, thus being able to act as prodrugs.

In the present specification, the term alkyl includes single and branched chain radicals, but references to individual radicals such as propyl should be understood to encompass only the single (normal) chain radical with branched chain isomers such as isopropyl V being specifically referred to. .

Halo as used in this specification generally means fluorine, chlorine, bromine or iodine.

It will be recognized by those skilled in the art that many of the compounds shown in the present specification can exist and be constructed in various tautomeric forms, and it should be understood that all references to any particular structure include its various tautomeric forms.

Particular values of (1-5C) alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl and neopentyl.

Λ

Particular values of R ^x to Ir with the meaning of perfluoroalkyl- (1-3C) include trifluoromethyl, pentafluoroethyl and heptafluoropropyl.

Particular values from ít to R ⁴ with the meaning of halo include fluorine, chlorine, bromine and iodine.

More particular values of alkyl- (1-50) include methyl, ethyl and propyl.

More particular values of R ^ to R ^ with the meaning of perfluoroalkyl- (1-30) include trifluoromethyl and pentafluoroethyl.

4

More particular values from R to R with the meaning of halo include fluorine, chlorine and bromine.

2 3 4

Preferred values of R, R, R and R include hydrogen and halo.

Preferred values of alkyl- (1-50) include methyl and ethyl.

3

Especially preferred values of R and R include hydrogen, fluorine, chlorine and bromine.

Δ

Especially preferred values of R and R include hydrogen.

Preferred compounds of the present invention include:

8-chloro-2,5-dihydro-2,5-dioxo-3-hydroxy-lH-benz / ^a ~ b_7 benzazepine;

7-chloro-2,5 ”dihydro-2,5-dioxo-3-hydroxy-1H-benz /” b-7azepine;

S-bromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / bazazine;

8-fluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / ^- 7azepiiia;

6.8- dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / benzazepine;

6.8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / benzazepine;

6.8- difluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-

- b enz / ^- b__7 az and pina;

and its enol-alkyl- (1-5C) ethers (i.e., compounds of the formula II in which it is alkyl- (1-50), especially the methyl and ethyl enol-ethers.

The Henz _J / ^az ~ b_7 epinas of formula I may be prepa Radas by processes which include processes known in the chemical ca TECNI for the production of compounds structurally abnormal GOS. Such processes for the preparation of a benzyl ^- b ^- 7azepine of formula I as defined above are provided as additional aspects of the present invention and are illustrated by the following procedures in which the meanings of the generic radicals are as defined above, unless otherwise stated. Such a process can be carried out, generally, by reacting a compound of formula II, wherein Ir and an alkyl- (1-50) group, such as methyl or ethyl, with a boron trihalide.

If they are not commercially available, raw materials for procedures such as those

previously described can be prepared by procedures that are selected from standard organic chemistry techniques, techniques that are analogous to the synthesis of known structurally similar compounds, or techniques that are analogous to the procedure described above or the procedures described in the examples.

A compound of formula II can be prepared by reacting a corresponding alkyl enol-ether of formula III with sodium azide in pure trifluoromethanesulfonic acid or concentrated sulfuric acid (Schmidt reaction) at a temperature between approximately 0 ° C and room temperature. Trifluoromethanesulfonic acid is preferred in cases

4,, 5, wherein one or more of the groups R to R is halogen. R is preferably methyl or ethyl to facilitate the Schmidt reaction.

A methyl enol-ether of formula III can be prepared by reacting a corresponding hydroxy-naphthoquinone of formula IV with a corresponding alcohol of formula R fórmulaOH, such as methanol or ethanol, in the presence of a suitable acid such as chloride anhydrous hydrogen. The hydroxy-naphthoquinones of formula IV can be prepared by oxidation of a corresponding formula of formula V or formula Va. The oxidation can be carried out conveniently as a process without changing the reactor in a suitable solvent such as tert-butanol and in the presence of a suitable hase such as potassium tert-butoxy, with oxygen bubbled through the reaction mixture. It will be recognized by those skilled in the art that suitable variations can be implemented in phases or by changing the reactor in the process without changing the reactor.

Many tetralones of formula V and / or Va suitable for use in the present invention are either commercially available or can be prepared by procedures already known in the art. for example, a 1-tetralone of formula V can be prepared by cycling a corresponding acid of the formula

VI under acidic conditions, for example with polyphosphoric acid with the application of heat. A 2-tetralone of the formula Va can be prepared by inserting ethylene in the corresponding phenylacetic acid chloride of the formula Via, followed by cyclization, according to the general method of Rosowsky et al, J.Org. Chem., 33, 4283 (1963).

The compounds of the formula VI can be prepared by reducing a corresponding ketone, for example, by reducing a compound of the formula VII by methods known in the art, e.g. ex. a Wolff-Kishner reduction for the reduction of carbonyl groups using hydrazine and base.

The compounds of the formula Via can be prepared by converting a benzyl alcohol of the formula VIII (X = OH) to a corresponding benzyl chloride (1 = 01) (eg, by reaction with an appropriate reagent such as thionyl chloride) followed by reaction of the benzyl chloride thus formed with a suitable alkali metal cyanide (eg sodium cyanide) to effect the displacement of chloride cyanide and thereby form a corresponding benzyl cyanide (1 = 011). An acid of the formula Via can be prepared as is known in the art by hydrolysis of benzyl cyanide under acidic conditions.

Alternatively, acids of the formula Via can be formed by brominating a toluene corresponding to formula VIII where X = H to form the corresponding benzyl bromide (X = Br), followed by displacement with cyanide as described above to form Via acid.

Note that many enol-ethers of formula III can also be prepared along the lines described in general in S.T. Perri et al., Org. Syn., 69, 220 and in J. M. Heerding and H. W. Moore, J. Org. Chem., 56, 4048-4050, (1991). The synthesis is generally illustrated in Scheme I below (presents

on the pages following the Examples). The organo compound. lithium 10 can be reacted with the semisquarate compound or semisquaric acid 12 to thereby give 4- (disubstituted aryl) -3-alkoxy-4-hydroxy-2-cyclobutenone 14. Note that the semisquarate compound 12 can be easily obtained, as described in Heerding and Noore, supra, by treating a dialkyl squarate (such as diethyl, diisopropyl or dibutyl squarate, all commercially available from Aldrich) with a suitable reducing agent such as lithium hydride and tri-tert-butoxyaluminium, followed by hydrolysis of intermediate 13 thus obtained in hydrochloric acid gas. Compound 14 can in turn be converted, by heating in a suitable solvent such as xylene, to hydroquinone 16. Hydroquinone 16 can then be oxidized (e.g. with ferric chloride) to the corresponding naphthoquinone 18. If necessary before conducting the Schmidt reaction on naphthoquinone, quinone naphthone 18 can be trans-transfected, for example with methanol hydrochloric acid, thereby producing methoxy-naphthoquinone 20 with formula III.

Examples of suitable pharmaceutically acceptable salts are salts formed with bases that form a physiologically acceptable cation, such as an alkali metal (for example, sodium and potassium), an alkaline earth metal, aluminum and ammonium salts, as well as salts prepared with organic bases such as triethylamine, morpholine, piperidine and triethanolamine. Care should be taken to avoid metals and / or metal compositions that may result in metal-catalysed decomposition of the active ingredient.

When benz / b___7azepine of formula I is used to intervene therapeutically after an attack, it is generally administered in the form of an appropriate pharmaceutical composition containing a benz _ / “b__7azepine of formula I as defined above together with a diluent or carrier. pharmaceutically acceptable, the com-

position adapted to the particular route of administration chosen. Such compositions are provided as an additional aspect of the present invention. They can still be obtained using conventional procedures and excipients and binders and can be found in various dosage forms. For example, they can be in the form of tablets, capsules, solutions or suspensions for oral administration; in the form of suppositories for rectal administration; and in the form of sterile solutions or suspensions for administration by intravenous or intramuscular injection or by infusion.

The dose of compound of formula I that is administered will necessarily be varied according to principles well known in the art taking into account the route of administration, the severity of the ischemic condition, and the size and age of the patient. In general, a compound of formula I will be administered to a warm-blooded animal (such as man) so that an effective dose is received, for example a cLose in the range of about 0.1 to about 10 mg / kg of body weight intravenously.

It will be apparent to those skilled in the art that a compound of formula I can be co-administered with other therapeutic and prophylactic agents and / or drugs which are not medically incompatible with it.

The actions of the compounds of formula I as antagonists at the glycine receptor of the EF1DA receptor complex can be shown by normal tests such as the H 2 / - glycine binding test, by in vitro functional tests such as tests for the measurement of guinea pig ileus contractions caused by glutamate, and in vivo tests such as carotid occlusion-induced allergy in the gerbil model.

In the / ”^ 7 -7-glycine binding test, neuron synoptic membranes are prepared from rats

Adult Sprague-Dawley male (about 250 g). Cortices and hippocampi just dissected in 0.32 M sucrose (110 mg / ml) are homogenized. Synaptosomes are isolated by centrifugation (1000 xg, 10 min), the supernatant is added (20,000 xg, 20 min) and resuspended in double distilled water. The suspension is centrifuged for 20 minutes at 8000 xg. The resulting supernatant and buffer layer are washed twice (43,000 xg, 10 min, resuspension in doubly deionized water). The final aggregate is quickly frozen (dry ice / ethanol bath) under doubly deionized water and stored at -70 ° C.

On the day of the experiment, thawed synaptic membranes are homogenized with a Brinkmann Polytron tissue homogenizer (tm, Brinkmann Instruments, Westbury, N.

Y.) in 50 mH tris (hydroxymethyl) -aminomethane citrate, ple 7.1. The membranes are incubated with 0.04% Sufact-AMPS Σ100 (tm, Pierce, Rockford, IL) in buffer for 20 minutes at 37 ° C and washed six times by centrifugation (48 OOOxg, 10 min) and resuspended in buffer. The final aggregate is homogenized at 200 mg net weight / ml of the buffer for the binding test.

For the binding of Γ ⁵ η_7 -glycine at the N-methyl-D-aspartate receptor, 20nM / ~ ^ H_7-glycine (40-60 Ci / / mmol, New England Nuclear, Boston, MA) is incubated with suspended membranes, 50 mH tris (hydroxymethyl) aminomethane citrate, pH

7.1 for 30 minutes at 4 ° C. 1 mM glycine is used to define non-specific binding. Bound glycine bound and isolated from free using a Brandel cell collector (Biomedical Research and Development Laboratories, Gaithersburg, MD) for vacuum filtration over glass fiber filters (What man GP / B from Brandel, Gaithersburg, MD) pre-soaked in 0.025% polyethyleneimine. The samples retained in the glass fiber filters are rinsed 3 times with a total of 2.5 ml of cold buffer. Radioactivity is determined by counting scintillations in the liquid phase. The CI values are obtained 11 -

by a least squares regression of a logit-log transformation of the data. Typical values for compounds of the present invention are illustrated by the compound of

Example 1 and Example (IC | _ _O = 30 nanomolar (nM)), Example 3 (ΙΟ ^ θ la (ΐΟ ^ θ = 1.0 micromolar (μΜ)).

For guinea pig ileum contractions caused by glutamate, the methodology is as previously described (Luzzi et al., Br. J. Bharmacol., 95, 1271-1277 (1989). The longitudinal muscle and the associated myenteric plexus are removed and placed in modified oxygenated Krebs-Henseleit solution (iTaCI 118 mM, KC1 4.7 mM, Ca01 ₂ 2.5 mM, KH ₂ ? 0 ₄ 1.2 mM, NaHCO ^ 25 mM and glucose 11 mM). suspended on glass rods in organic baths under a tension of 0.5 g. After an initial depolarization with 80 mM potassium to remove a possible blockage of the KMDA receptor channel complex with magnesium, contractive responses with glutamate are elicited. 100 μΜ Isometric mechanical responses are recorded The tissues are balanced for at least 2 hours before adding compounds.

A dose-based response curve is generated for the effect of the unknown on the magnitude of contractions caused by glutamate. Contractions caused by glutamate are generated at 20 minute intervals, with the test compound added 5 minutes before glutamate. The magnitude of the contraction with each dose of the unknown and expressed in relation to the control, the third contraction caused only by glutamate 100 ρΆ in the same tissue bath. 0 - ^ 50 θ obtained by a least squares regression of a logit-log transformation of the data. Typical values for the compounds according to the present invention are illustrated by the compound of Example 1 (IC ^ _O = 0.11 μΜ) and Example 3 (10 ^ q = = 1.0 µm).

After the last contraction for the response curve

depending on the dose, 100 µg glycine is added to the bath 10 minutes after the previous addition of glutamate. 10 minutes later the dose of the estimated ΙΟγθ of the test compound is added and 10 minutes later, glutamate is used to cause contraction. Glycine inversion ”is the ability of glycine to compete with the unknown and to avoid the inhibition previously observed by the dose of the unknown.

During in vivo testing using the ischemic gerbil model, Mongolian gerbils are anesthetized, female ducts (50-70 g) with 2% 3% halothane · The bilateral bilateral carotid arteries in the neck are exposed and occluded with microaneurysmic clamps . After 10 minutes (unless specified), the staples are removed and the blood flow through the carotid arteries is restored and the skin is sutured. Test compounds are administered intraperitoneally both before and after occlusion, for example 4-5 minutes before and 5 minutes after occlusion of the carotid arteries. A group of comparison animals are treated in the same way except that the arteries are not stapled. The most notable observations regarding behavior along with motor activity are recorded for 2 h on the first day (24 h) after occlusion. After 4 days, the subjects are sacrificed (beheading), the brain is removed, fixed, sectioned and stained with hematoxylin / eosin and cresyl violet.

The sections of the brain are classified with respect to neuronal damage in the hippocampus using the following classification scale:

= undamaged, normal = slight damage (up to 25%) - restricted CAl / subicle border = moderate damage (up to 50%) - obvious damage, restricted to less than half the CAI field = marked damage (up to 75%) - involving more than 13% of the CAI field = damage extending beyond the CAI field

The results can be recorded as the percentage of neuroprotection provided by a particular dose and dosage regimen.

Sections (7 microns) of each brain are evaluated. Asymmetrical damage can occasionally be observed and the classification given is the average of both sides. The average score for brain damage is recorded, and the score for damage in the drug-treated group is compared with the vehicle-treated group using the Wilcoxcon-Rank Sum test.

Typical values in this test for compounds according to the present invention are illustrated by the following results: for the compound of Example 1, 57% neuroprotection (relative to the control group of comparison animals) when dosing is applied twice with 20 mg / kg body weight intraperitoneally (ip) according to the regime previously explained; 44% neuroprotection when the dosage is, 30 mg / kg of body weight ip three times at 15, 30 and 45 minutes after ischemia induction; for the compound of Example 3, 83% neuroprotection when the dosage is applied twice with 30 mg / kg of body weight ip according to the regime explained above; for the compound of Example la, 78% neuroprotection when the dosage is applied twice with 20 mg / kg of body weight ip according to the previously explained regime.

The present invention will now be illustrated by the following non-limiting examples in which, unless otherwise indicated:

(i) temperatures are given in degrees Gelsius

(° C); the operations were carried out at room or laboratory temperature, that is, at a temperature in the range of 18 to 25 ° C;

(ii) solvent evaporation was carried out using a rotary evaporator under reduced pressure (600 to 4000 Pascal; 4.5 to 30 mm Hg) with a bath temperature up to 60 ° C.

(iii) flash chromatography was performed on a 40 µM silica gel flash chromatography flask obtained from J.T. Baker; thin layer chromatography (CGF) was performed on Analtech 0.25 mm silica gel GHLF plates, obtainable from Analtech, Newark, DE, USA;

(iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;

(V) the melting points are not corrected and (dec) indicates decomposition; the melting points given are those obtained for the materials prepared as described; due to polymorphism it is possible to isolate materials with different melting points in some preparations;

(vi) all final products were essentially pure by CGF and had nuclear magnetic resonance (NMR) spectra and satisfactory microanalytical data;

(vii) yields are given for illustration only;

(viii) reduced pressures are given as absolute pressures in Tascai (Pa); other pressures are given as manometer pressures in bar;

(ix) chemical symbols have their usual meanings; the following abbreviations were also used; v (volume), p (weight); mp (melting point), L / liter (s) _7, mL (milliliters), mM (millimoles), g / ”gram (s) _7, mg / milligrams) / 7;

(x) solvent ratios are given in terms of

- 15 1

volume: volume (v / v), unless otherwise specified; and (xi) conventional acronyms such as NMR (nuclear magnetic resonance), THR (tetrahydrofuran), DMSO (dimethylsulfoxide), DMP (dimethylformamide), TEA (trifluoroacetic acid), and so on are used.

Example 1

8-Chloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / ”b_7a2epine Eormula I: ΛΑΑη; P? = C1 7

8-Chloro-2,5-dihydro-2,5-dioxo-3-methoxy-1H-benz / ”7 -azepine / Formula II: R ¹ = R ² = R 4 = H; R ⁵ = C1; R ⁵ = = 0Ή ^ _7 (0.0789 g, 0.332 mM) to a solution of 1.01 ml of boron tribromide (1.0 M, CE ^ Olg) in 1.8 ml of methylene chloride dried under nitrogen . The suspension was stirred at room temperature for 0.42 hours. The reaction mixture was poured into 7 ml of saturated aqueous sodium bicarbonate and stirred for 0.25 hours. The homogeneous solution was then adjusted to pH = 5 by slowly adding concentrated hydrochloric acid. The precipitate was filtered under vacuum and washed with water to give 0.0633 g (92%) of white solid which was recrystallized from 5 ml of DMF and 1 ml of water. After cooling in an ice bath, the solid was collected by vacuum filtration, washed with water and dried under vacuum at 100 ° C and 15 Pa to give g (75%) product; mp 308.5-310.5 (dec); NMR (DMSO-dg, = 2.0 Hz), 7.31 (dd, (s, 1H);

0.056 g

300 MHz): 11.57 (s, 1H, NH), 10.86 (brs, 1H, OH), 8.04 (d , ^J = ⁸ ortho> ^7Hz '>^{7> 54 J} _m ^J ortho ^{= S} eta ' ^{7, J} me-ta ^2.0

Analysis for Ο ^ θΗ ^ ΟΙΝΟ ^: Calculated:

Found:

Hz), 6.41

0,

0,

53 * 71; H,

53.30; H,

2.70; N, 6.26

2.74; N, 6.29

Examples 1 to 1 describe and disclose a sequential synthetic path to prepare the intermediate used to prepare the title compound of Example 1.

Example la (Procedure A)

8-01oro-2,5-dihydro-2,5-dioxo-3-methoxy-1H-benz / 7azepine / Formula II: ΛΑΛη; R ³ = C1; R ⁵ = CH ₃ 7

7-chloro-2-methoxy-1,4-naphthoquinone / Formula III was added: R ¹ = R ² = R ⁴ = H; R ⁵ = C1; R ⁵ = CH „_7 (0.71 g, 3.2 mM) a

4.1 ml of concentrated sulfuric acid frozen in an ice bath. The cold red solution was stirred under nitrogen and sodium azide (0.23 g, 3.5 mM) was added. The reaction mixture was kept in an ice bath for 0.33 hours and then allowed to warm up to room temperature and maintained in that manner for one hour. The reaction mixture was cooled in an ice bath and an additional portion of sodium azide (0.21 g, 3.2 mM) was added. After 0.33 hours the mixture was allowed to warm to room temperature for 20 hours. Again the mixture was cooled in an ice bath and sodium azide (0.21 g, 3.2 mM) was added; the mixture was kept in an ice bath for 0.33 hours and then at room temperature for 68 hours. The reaction mixture was then poured into 200 ml of iced saturated aqueous sodium bicarbonate. The resulting precipitate was filtered, washed with water to give after drying under vacuum (25 ° C, 15 Pa) 0.343 g (45%) of dark solid. The solid was recrystallized from 3 ml of DMF and 1 ml of water to give 0.2 g (26%) of a white solid; BIR (J> SO-d _g , 250 MHz): 11.39 (s, 1H, nH), 7.93 (d, 1H, J _{o3? TQ} = 8.8 Hz), 7.47 (d, IH , J _target = 1.7 Hz), 7.28 (dd, 1H, J _ortQ = 8.8 Hz, = 1.7 Hz) 6.35 (s, 1H),

3.30 (s, 3H).

Example, la (Procedure B)

8-Chloro-2,5-dihydro-2,5-dioxo-3-methoxy-1H-benz / b / 7azepine / Formula II: R ¹ = R ² = R ⁴ = H; R ⁵ = 01; R ⁵ = CH ₃ 7

7-chloro-2-methoxy-1,4-naphthoquinone / Formula III was added: R ¹ = R ² = R ⁴ = H; R ³ = C1; R ⁵ = CH ₃ _7 (14.74 g, 66.2 mM) to chilled trifluoromethanesulfonic acid (153 ml) in a

ice under nitrogen. The solution was stirred under nitrogen and sodium azide (4.74 g, 73.0 mM) was added. The reaction mixture was kept in an ice bath for 0.33 hours and then allowed to warm up to room temperature and maintained in this manner for 90 hours. The reaction mixture was cooled in an ice bath and an additional portion of sodium azide (2.15 g, 33.1 ml) was added. After 0.08 hours the mixture was left, at. warm to room temperature for 19 hours. The reaction mixture was then poured into ice-cold aqueous sodium bicarbonate (153 g, 1.82 M in 2.3 L). The resulting precipitate was filtered, washed with water to give after drying under vacuum (25 ° C, 15 Pa) 13.83 g of a brownish solid. The solid was recrystallized from 300 ml of hot DMF. After cooling in an ice bath, the solid was filtered, washed with cold DMF followed by water to give after drying under vacuum (25 ° 0, 15 Pa) 8.12 (52%) of a light brown solid; mp 340-342 (dec).

Analysis for Ο- ^ ΗθΟΙΝΟ ^:

Calculated: C, 55.60; H, 3.39; H, 5.89

Found: 0, 55.35; H, 3.3'8; N, 6.07

Example lb

--- ---- r- <12 1

7-Chloro-2-methoxy-1,4-naphthoquinone Formula III: R = R = R '= H; R ⁵ = C1; R ⁵ = CH ₅ 7

7-chloro-2-methoxy-1,4-naphthoquinone / “FormulaHLR ¹ = R ² = R ⁴ = R ⁵ = H; R ⁵ = C1-7 (0.73 g, 3.5 mM) to 14 ml of 4% (w / w) hydrogen chloride in methanol under nitrogen at room temperature. The solution was heated at reflux temperature for 0.5 hours. After cooling to room temperature, a precipitate formed which was filtered and washed with methanol. After drying under vacuum (25 ° C, 15 Pa) 0.72 g (92%) of an orange solid were obtained; NMR (DMS0-dg, 250 MHz) 8.10 (d, 1H, J _target «2.2 Hz) 8.04 (d, 1H, J _Qrto = 8.3 Hz), 7.71 (dd, 1H, J _Qrto = 8.3, = 2.2 Hz), 6.19 (s, 1H),

3.92 (s, 3H).

Example 1c

9 Λ

7-Chloro-2-hydroxy-1,4-naphthoquinone / Formula IV: R = R = R = H; r ⁵ = ci 7

7-chloro-1-tetralone / Formula V was added: pA = r2 = r4 = H; r ⁵ = 01_7 (27.56 g, 0.153 mole) dissolved in 445 ml · of dry tert-butanol over a period of one hour to a solution of recently sublimated potassium tert-butoxide (102.7 g, 0.916 mole) in 1.15 l · of dry tert-butanol held with oxygen at room temperature. Oxygen was bubbled through. solution for two hours after completion of the addition. The mixture was poured into stirred hydrochloric acid (1.9 L ·, 2N) and extracted with diethyl ether. The ether extracts were concentrated in vacuo to give a yellow solid which was triturated with ethyl acetate. The solid was filtered, washed with water and dried in vacuo (25 ° 0, 15 Ra). 10.5 g of the yellow solid was then taken in 0.5 L of hot ethyl acetate and the solution was concentrated to 50 ml. Crystallization was started by cooling the solution in an ice bath. The solid was filtered, washed with cold ethyl acetate and hexane. After drying under vacuum (25 ° C, 15 Pa), 7.10 g (22%) of yellow plates were obtained; mp 215-216.5 ° 0.

The 1-tetralones were prepared by the method of Hewman and Seshadri, (MS Newman and S. Seshadri, J. Org. Chem., 27, 76 (1962). The 2-tetralones were prepared by the method of Rosowsky et al, J. Org. Chem., 33, 4288 (1968) The 5,7-dibromo-2-tetralone was prepared using 3,5-dibromo benzyl bromide prepared as follows.

3,5-dibromobenzyl bromide

3,5-dibromotoluene (78.92 g, 0.316 mole) was dissolved in 1.27 D of carbon tetrachloride; to this solution, N-bromosuccinimide (61.65 g, 0.346 mole) was added at

rature. A portion of dibenzoyl peroxide (0.6 g, 0.003 equivalents) was added and the solution was heated to reflux temperature for 2.5 hours. The reaction mixture was cooled to room temperature, filtered and the solvent was removed in vacuo to give a solid. The solid was dissolved in 200 ml of warm hexane, filtered and cooled to room temperature. The product crystallized; the crystals were filtered and washed with cold hexane and dried, obtaining 45.15 g (44%) of 3,5-dibromobenzyl bromide. • ^ - «(CDC ^); 6 7.6 (1H), 7.47 (2H), 4.36 (2H).

Example ld

7-Chloro-1-tetralone / formula V; ΛΛΛη; R ³ = C1 7

4-chlorophenylbutyric acid / formula VI was added; Λε ² = Κ ⁴ = Η; R ⁵ = C 1-7 (26.62 g, 134.0 mM) to 150 g of hot polyphosphoric acid (90 ° C); the mixture was maintained at a temperature between 90 and 95 ° C for 0.33 hours. After cooling to room temperature, the reaction mixture was added to 400 ml of cold stirred water. The solution was allowed to warm to room temperature, depositing a precipitate. The solid was filtered, washed with water and dried in air, obtaining 22.3 g, (92%) of a pale yellow solid. The solid was recrystallized from 50 ml of toluene at -10 ° C. The crystals were collected and washed with cold toluene and then with hexane to give 13.13 g (75%) of pale yellow crystals; mp 100.3-101.1 ° C.

Example 4-chlorophenylbutyric acid / formula. VI: R ^ = R ² = r4 == H; B. ³ = C1_7 / ¹

4-Chlorobenzoyl-propionic acid / formula VII was dissolved: kW = R ⁴ = H; R ³ = C1-7 (49.94 g, 234.9 mM) under nitrogen in 320 ml of triethylene glycol. to the stirred solution at room temperature was added potassium hydroxide (44.5 g, 794 mM) followed by 98% hydrazine hydrate (29.0 g, 580.0

π $ ΐ). The mixture was heated to reflux temperature (142 ° C) for 2 hours. Water and hydrazine hydrate were removed by distillation at atmospheric pressure; the reactor temperature rose to 195 to 200 ° C. After 0.5 hours at a temperature between 195 and 200 ° C, the mixture was cooled to room temperature, diluted with 520 ml of water. The aqueous solution was poured into hydrochloric acid (200 ml, 611) and subjected to an additional dilution with 200 ml of ice water. In this situation a solid formed which was filtered, washed with water and dried in vacuo (25 ° 0, 15 Pa) to provide 43.61 g (93%) of a white solid.

Examples 2 to 6

A series of 2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / β-7azepines of the formula. I was prepared according to procedures analogous to those presented in Example 1. Table I identifies each of these compounds by naming each individual substitute R '' ( ⁿ i ⁿ means an integer corresponding to the designation of the substituent in the formula) and presents analytical data regarding CHN and melting points for each. Table II also identifies each of the components synthesized and presents data related to NKR.

Examples 2a to 6a

Examples 2a to 6a correspond to intermediate methyl ethers of formula II used to prepare each of the corresponding compounds of Examples 2 to 6; Table III identifies each of the intermediaries and presents data η

referring to Πϊ-IJMR. Each of the methyl ethers was prepared according to procedures analogous to those presented in Example la, Procedure A or in Example la, Procedure B. The procedure employed for each intermediary is shown in Table III.

Examples 2b to 6b

Examples 2b to 6b correspond to the series of 2-methoxy-1,4-naphthoquinones of formula III used to prepare each of the corresponding intermediate methyl ethers of Examples 2a to 6a; Table IV identifies each, one of these compounds and presents data related to NMR,

Example 2nd

Example 2c (Table V) identifies the 6-chloro-2-hydroxy-1,4-naphthoquinone used to prepare the corresponding 6-chloro-methyl ether of Example 2b. The compound was prepared by a direct application of the J. M. Eyons and R. H. Thomson, J. Chem. Soc., 1953, 2910-2915. It is noted that Jbyons and Thomson confirmed that they had prepared a different isomer in their communication, but it is believed that the original attribution of these authors was not correct.

Examples 3c to 6c

Examples 3c to 6c correspond to the series of 2-hydroxy-1,4-naphth quinones of formula IV used to prepare each of the corresponding methyl ethers of Examples 3b to 6b; Table V identifies each of these compounds and presents NMR data.

3d to 4d examples

Examples 3d to 4d correspond to the series of 1-tetralones used to prepare the corresponding 2-hydroxy-1,4-naphthoquinones from Examples 3c to 4c; Table VI identifies each of these compounds and presents NMR data.

Examples 5d to 6d

Examples 5d to 6d correspond to the series of 2-tetralones of formula Va used to prepare the corresponding 2-hydroxy-1,4-naphthoquinones of Examples 3c to 4c; Table VII identifies each compound and presents data regarding

Example 7

The synthetic sequence for preparing the title compound of Example 7 (compound identified and shown in Table I and Table II) proceeds according to Scheme I (R = R R. = R = H; R = isopropoxy), and is described below:

5.7- Difluoro-2-methoxy-1,4-naphthoquinone (Compound 20)

A solution of 0.48 g (13.2 mM) of anhydrous hydrogen chloride in 15 ml of methanol was treated with 0.175 g (0.694 mM) of 5,7-difluoro-2-isopropoxy-1,4-naphthoquinone. The mixture was heated to the reflux temperature of the solvent for 0.33 hours, cooled to room temperature and concentrated in vacuo, yielding 0.13 g of the product. NMR (dmso-dg): $ = 7.8 (m, 1H), 7.68 (dd, 1H, _Dead J = 7.5 Hz), 6.31 (s, 1H), 3.86 (s, 3H) '.'

5.7- difluoro-2-isopropoxy-1,4-naphthoquinone (Compound 18)

A solution of 0.55 g (2.1 mM) of

5.7- difluoro-1,4-dihydroxy-2-isopropoxy-naphthalene in 20 ml of diethyl ether over 0.05 hours in a stirred solution at room temperature of 4.05 g (25 mM) of chloride ferric in 46 ml of water and 12 ml of isopropanol. The mixture was stirred for 0.75 hours and then extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered and concentrated to give 0.44 g of a solid

brownish which was recrystallized from 3 ml of warm acetic acid and a few drops of water. After cooling to room temperature, the solid was filtered, washed with acetonitrile and then with water before being dried under vacuum at room temperature to give 0.057 g of a yellow solid, mp 172.0-173.2 °; KMR (CDC ^): $ = 7.68 (dd, 1H), 7.15 (m, 1H), 6.09 (s, 1H), 4.55 (m, 1H), 1.45 (d, 6H).

5,7-difluoro-1,4-dihydroxy-2-isopropoxy-naphthalene (Compound 16)

A THF solution of 2-hydroxy-3-isopropoxy-2- (5,5-difluorophenyl) -3-cyclobutenone was diluted, see below, with 40 ml of p-xylene and then concentrated to 16 ml. The p-xylene solution was then diluted to a total volume of 40 ml with additional p-xylene and heated under argon at reflux temperature for 0.42 hours. The solvent was removed in vacuo to give 0.87 g of amber oil. MS (Cl, GH ^): m / e = = 255 (M% 1, peak base).

2-hydroxy-3-isopropoxy-2- (3,5-difluorophenyl) -3-cyclobutenone (Compound 14)

0.753 g (3.9 mM) of 3,5-difluorobromobenzene in 24 ml of dry distilled THF under argon were cooled to -75 ° and 2.34 ml of n-butyllithium (1.54 M in hexane) was added over 0.033 hours. The mixture was kept between -75 and -70 for 0.42 hours and then transferred via cannula to a -75 ° solution of 0.46 g (3.3 mM) of 3-isopro poxi-3- cyclobutene-1,2-dione in 60 ml of dry distilled THF over 0.17 hours. The solution was kept at -75 ° for 0.33 hours after which 1.4 ml of water were added and stirring was continued for 0.17 hours. The reaction solution was poured into a mixture of crushed ice and diethyl ether. The phases were separated and the aqueous phase extracted with additional diethyl ether. The combined organic extracts were

dried over sodium sulfate, filtered and concentrated to

3-isopropoxy-3-cyclobutene-1,2-dione (Compound 12)

7.38 g (36.9 mM) of 2,3-diisopropoxy-4-hydroxy-2-cyclobutenone in 116 ml of methylene chloride was stirred with 2 ml of concentrated hydrochloric acid at room temperature for 1 hour. The solution was neutralized and dried over potassium carbonate and sodium sulfate, filtered and concentrated in vacuo to give 5.14 g of a red oil. The oil was subjected to flash chromatography on SiOg (7.5 cm diameter x 10 cm column) using diethyl ether - hexane (1: 1) as the eluent. The concentration of the largest fraction gave 4.14 g (80%) of a yellow oil. ^Χ Η BMR (GD01 ₅ ): ô = 8.48 (s, 1H), 5.02 (m, 1H), 1.49 (d, 6H); MS (GI, CH ^): m / e = 141 (l7 + l), 99 (base peak)

2,3-diisopropoxy-4-hydroxy-2-cyclobutenone (Compound 13)

A 10.02 g (50.55 mM) solution of

3,4-diisopropoxy-3-cyclobutene-1,2-dione in 100 ml of dry distilled THF at -10 ° and treated over 0.66 hours with a 16.0 g solution (63.1 g mM) of lithium hydride and tri- (tert-butoxy) aluminum in 63 ml of TH? dry distillate, maintaining an internal temperature between -5 and -10 °. The temperature was maintained at -5 ° for an additional 0.5 hours. The reaction mixture was added to a stirred and saturated aqueous solution of sodium and potassium tartrate and 50 ml of diethyl ether. The organic layer was separated and the aqueous phase extracted with diethyl ether. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 8.12 g of yellow oil. The oil was subjected to chromatography on SiOg (7 cm in diameter x 8.5 cm in column) using diethyl ether / hexane (1: 1) as the eluant. The concentration of the larger fraction gave 7.38 g (73%) of

colorless oil. BIR (CDCl ^): = 4.9 (m, 3H), 2.65 (bs, 1H),

1.42 (d, 6H), 1.30 (m, 6H); MS (CI, CH ₄ ): m / e = 201 (ίΛ1), 159 (base peak).

EEEZPIO 8

The following are representative pharmaceutical dosage forms that contain a compound of formula I or formula II, for example as illustrated in any of the previous Examples, (hereinafter referred to as Compound Σ), for therapeutic or prophylactic use in humans ;

(a) mg tablets / tablet

Compound Σ 50.0

Mannitol, USP ............................ 223.75

Croscarmellose sodium .......... 6.0

Corn starch 15.0

Hydroxypropylmethylcellulose (HPMC), USP ..2,25

Magnesium stearate 3.0 (b) Capsules

Compound X ..... 10.0

Mannitol, USP 438.5

Croscarmellose sodium ........ 15.0

Magnesium stearate .... 1.5

The above formulations can be obtained by conventional procedures well known in the pharmaceutical art. The tablets can be coated by conventional means for enteric use, for example by forming a cellulose acetate-phthalate coating.

Example 9

The following is a description of a for26 -

injectable formulation prepared with the compound of Example 1.

A series of aqueous solutions of various concentrations of the compound of Example 1 (the '' Compound ') was prepared. An aqueous solution formulation suitable for intravenous administration containing 3.5 mg / mL- of the Compound by (1) dissolving Meglumine (N-methylglucamine) in water in an amount sufficient to prepare a solution of 19.5 mg / mL;

(2) dissolving the Compound in the solution in an amount sufficient to achieve the desired Compound concentration of 3.5 mg / ml; and (3) adding sodium chloride or dextrose in an amount sufficient to achieve isotonicity. Drug concentrations of less than 3.5 mg / ml were also prepared. The formulations were prepared using typical preparation procedures for parenteral products, for example using ultrasound treatment as needed to aid the dissolution effect of the Compound.

Claims (6)

Process for the treatment of neurological disorders characterized by administering to a mammal in need of such treatment an effective amount of a compound of formula I, a pharmaceutically acceptable salt of a compound of formula I or a compound of formula II, the formulas of which are presented below, in which 12 3 4 ~ R, R, R and R are independently selected from: hydrogen, perfluoroalkyl (1-30), halo, nitro and cyano; and R4 is a (1-50) alkyl group. - 2S - Process according to claim 1 characterized by: 12 3 4 R, R, R and R are independently selected from hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl and halo; and R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl and neopentyl. - 3- - Process according to claim 2 characterized by: R1, ^R2, and R ^ pJ are independently selected from hydrogen, trifluoromethyl and halo; and R is selected from methyl, ethyl and propyl. 4. ^A process according to claim 3, characterized by: 12 3 4 R, R, R and R are independently selected from hydrogen, fluorine, chlorine and bromine; and R is selected from methyl and ethyl. _ 5th _ Process according to claim 1, characterized in that said compound is selected from: S-chloro-2,5-dihydro-2,5-dioxo-3 "hydroxy-lH-benz / ^{- az} b_7 ®pi in; 7-chloro-2,5-dihydro-2,5-dioxo-3-hydroxy-U-I-benz / ”b__7a2epine; S-bromo-2,5-dihydro-2,5-d.ioxo-3-hydroxy-1H-benz / -bazazine; 8-fluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / ”h_7azepine; 6.8- dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / azepine; 6.8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / b7-azepine; 6.8- difluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / azepine; their pharmaceutically acceptable salts and alkyl (1-5C) -enol-ethers. - Pharmaceutical compositions for the treatment of neurological disorders characterized by containing a compound of formula I, a pharmaceutically acceptable salt of a compound of formula I or a compound of formula II, the formulas of which are given below, in which 12 3 A ~ R, R, R and R 'are independently selected from; hydrogen, perfluoroalkyl (1-3C), halo, nitro and cyano; and R · 'is an alkyl group (1-50) and a pharmaceutically acceptable carrier or diluents. - 7 ^g - Composition according to claim 6 characterized by: 12 3 A R, R, R and R 'are independently selected from hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoro propyl and halo; and R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl are neopentyl. - Sa - Composition according to claim 7 characterized by: 1 2 * 5/1 R, R, R ⁹ and Pl are independently selected from hydrogen, omethyl trifluid and halo; and R is selected from methyl, ethyl and propyl. _ ga _ Composition according to claim 8 characterized by: 1 ο · ζ R, R, R ⁹ and R 'are independently selected from hydrogen, fluorine, chlorine and bromine; and R is selected from methyl and ethyl. Composition according to claim δ, characterized in that said compound is selected from: 3-chloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / benzazepine; 7-chloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / ”b__7” azepine; 8-broffio-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz / "b_7azepine; 8 "fluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-11-benz / benzazazin; 6.8- dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzylbazoline; 6.8-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benz2b_7azepine; 6.8- difluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzylbenz7azepine; its pharmaceutically acceptable salts and alkyl (1-50) -enolethers. - llê Compound of formula I or formula II, whose formulas are presented below, characterized by: R, R ^, R ⁹ and R ^ are independently selected from: hydrogen, perfluoroalkyl (1-30), halo, nitro and cyano; and R4 is a (1-50) alkyl group; with the proviso that R and R are not both (independently) selected from the group consisting of hydrogen and halo antigen when R ^r and R are hydrogen; and pharmaceutically acceptable salts of the compounds of formula I. Compound according to claim 11, characterized by: R ² , R ² and R 2 are independently selected from hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoro propyl and halo; and R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl and neopentyl. - 13 ^§ - A compound according to claim 12 characterized by: 12 3 4 R, R, R and R are independently selected from hydrogen, trifluoromethyl and halo; and R is selected from methyl, ethyl and propyl. -14ã - A compound according to claim 13 characterized by: 1 2 * 2A R, Fl and λ are independently selected from hydrogen, fluorine, chlorine and bromine; and R is selected from methyl and ethyl. -15 & - Compound according to claim 11, characterized in that it is selected from: 6.8- dichloro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzyl-7-azepine; 6, S-dibromo-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzyl-7azepine .; 6.8- difluoro-2,5-dihydro-2,5-dioxo-3-hydroxy-1H-benzb-7azepine; and its (1-5C) alkyl-enol-ethers. - 163 - Process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof according to any of claims 1 to 3, characterized in that a compound of formula II is reacted with a boron trihalide; and then, if a pharmaceutically acceptable salt is desired, reacting the compound of formula I with an appropriate base that gives rise to a physiologically acceptable cation. - 173 - Process for the preparation of a compound of formula II according to any of claims 1 to 3, characterized in that the corresponding alkyl enol ether of formula III is reacted with sodium azide in tcifluoromethane.sulfonic acid, pure or in acid concentrated sulfuric. - 183 - Compound selected from: 8-chloro-2,5-dihydro-2,5-dioxo-3-hydroxy-lH-benz / ^_ b_7azepina; 7-chloro-2,5-dihydro-2,5 "dioxo-3-hydroxy-1H-benz / -bazazine; 8-bromo-2,5-dihydro-2,5-dioxo-3-hydroxy-lH-benz / ^_ b_7azepina; 8-fluoro-2,5-b.idro-2, S-dioxo-S-hydroxy-lH-benz / ^- b_7azepina; and their pharmaceutically acceptable salts and alkyl (1-5C) -enol-ethers.